**3. Diabetic foot ulcers (DFUs)**

#### **3.1 Risk factors**

The main risk factors of DFUs include DM duration and high HbA1c [82–88]. The EURO-Diab group has identified hypertension, smoking and lipid disorders (hypertriglyceridemia, hypercholesterolemia) as additional risk factors [82, 83]. In Western countries, the male sex appears to be more commonly affected, with a risk ratio of 1.6. The co-existence of other microvascular complications (DR, nephropathy) increases the risk of DFUs.

Precipitating trauma is important. However, history of trauma is only identified in 48% of patients with DFUs. By contrast, foot injury without an apparent cause usually results from repeated minor injuries by inappropriate footwear [88–90].

Amin and Doupis have estimated that 45-60% of DFUs are mainly due to neuropathy, while 45% of DFUs are due to both diabetic neuropathy and peripheral arterial disease [87]. Like DR, diabetic neuropathy is also a very frequent DM complication and its prevalence increases with DM duration [90]. The other important driver of DFUs is ischemia from peripheral arterial disease (PAD). Visual impairment, foot deformities and past history of DFU also increase the risk of DFUs [85, 86].

#### **3.2 Pathophysiology**

The underlying mechanisms of DFUs include diabetic neuropathy, PAD and infection.

Diabetic neuropathy may affect the motor, sensory and autonomic nerves. Thickening of the basement membranes, endothelial hyperplasia in the vasa nervorum lead to thinning of the vascular lumen and secondary ischemia [90, 91]. On the other hand, metabolic disorders caused by chronic hyperglycemia, with the formation of AGEs, polyol pathways, increased oxidative stress levels and enzymatic activation of PKC also have direct toxic effects on nerve fibers.

Autonomic neuropathy causes arteriolo-venular shunts with secondary decreased blood flow in capillaries, but also anhidrosis, resulting in dry skin, thin, prone to cracking and ulceration. Sensory neuropathy leads to sensory (inability to feel warm/cold, pain, pressure), rendering the foot prone to undetected acute or chronic traumas [90, 91]. Motor neuropathy leads to imbalance between plantar flexors and extensors, with characteristic deformities, such as hammer toe, claw toe etc, and leading to high planter pressures in some small foot areas [92–94].

PAD leads to lower-extremity ischemia. In diabetes, it is usually located in the infra-popliteal arteries, less so at the iliofemoral level [89, 95]. Ischemia portends even more ominous outcomes [91, 96].

Pesently, micro and macrocirculatory disorders are considered not as separate entities, but more as a continuum in DM [97], neovascularization of vasa vasorum, with secondary hemorrhages and platelet aggregation facilitating the progression of atherosclerosis and intraluminal obstruction.

DFUs are frequently infected. The most common germs involved are staphylococci and streptococci, but deep infections are usually polymicrobial including gram positive, gram negative and even anaerobic germs [98, 99]. Chronic hyperglycemia and chronic hypoxia predispose to severe infections [99].

#### *3.2.1 Clinical signs-staging systems*

DFU represents any full-thickness ulcer below the ankle in DM. The initial signs and symptoms depend on the pathophysiological mechanism involved (neuropathy and/or PAD). Subjects with diabetic neuropathy are usually initially asymptomatic, but a minority of them may later develop neuropathic symptoms (numbness, paresthesia, lancinating or burning pain) with nocturnal exacerbation. In the event of PAD, intermittent claudication or even ischemic rest pain and gangrene may develop (**Figure 8**).

Usually, DFUs develop in an area exposed to increased pressure, with a nonhealing tendency, often neglected in early stages due to diminished pain sensation. In the vent of infection, signs of local inflammation may be added (redness, swelling, pain, pus secretion etc).

Several staging systems were developed in order to characterize the pathogenic pathway and the severity and extension of ulcer. The International Working Group on the Diabetic Foot Risk Classification System (IWGDF) refers mainly at the severity of neuropathy and coexistence or not of the peripheral ischemia [100], while the Wagner classification describes the extension and depth [101] (**Tables 4** and **5**).

**265**

**3.3 Diagnosis**

**Table 5.**

**Figure 8.**

**Table 4.**

*(Dr. Dragos Serban's private collection).*

*IWGDF risk classification [96].*

Grade 0 Intact sensation Grade 1 Diminished sensation

arterial disease Grade 3 Previous/present ulcer or amputation

cellulitis or abscess

Grade 5 Gangrene extended to midfoot/hindfoot

Grade 0 No ulcer in high-risk patients

cellulitis.

Grade 1 Superficial ulcer

Grade 4 Forefoot gangrene.

*3.3.1 Clinical examination*

*Wagner Classification of DFU [101].*

*Microvascular Complications of Diabetes Mellitus: Focus on Diabetic Retinopathy (DR)…*

*Distal toe gangrene and extensive infection and inflammation at the level of the forefoot and mid foot* 

Grade 2 Diminished sensation+ foot deformities (hammertoes, claw toes) +/-peripheral

Grade 2 Ulceration involving tendons, ligaments, muscles, joints, not exposed to bone, without

Grade 3 Deeper ulcers, with frequent bone complications of osteomyelitis, abscesses or

Patient history is necessary to provide information on DM duration, glycemic

*Evaluation of sensory neuropathy* is very important to establish whether the patient has lost the protective sensation, making him prone to accidental trauma. Hot/cold discrimination, pain perception, light touch and vibration perception, as well as protective sensation must be tested [95–99]. The latter is best assessed by the 10 g Semmes Weinstein monofilament or the measurement of the vibration perception

Clinical examination should look for skin disorders, foot deformities, nail lesions, blisters etc. also be documented. It must also include an evaluation of neuropathic deficits, PAD and infection. Signs of limb threatening infection include bullae, ecchymoses, soft tissue crepitus and rapid spread of infection [102, 103].

control, associated risk factors and any prior lesions/amputations.

*DOI: http://dx.doi.org/10.5772/intechopen.96548*

*Microvascular Complications of Diabetes Mellitus: Focus on Diabetic Retinopathy (DR)… DOI: http://dx.doi.org/10.5772/intechopen.96548*

#### **Figure 8.**

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

**3.2 Pathophysiology**

even more ominous outcomes [91, 96].

*3.2.1 Clinical signs-staging systems*

ing, pain, pus secretion etc).

atherosclerosis and intraluminal obstruction.

cemia and chronic hypoxia predispose to severe infections [99].

infection.

Amin and Doupis have estimated that 45-60% of DFUs are mainly due to neuropathy, while 45% of DFUs are due to both diabetic neuropathy and peripheral arterial disease [87]. Like DR, diabetic neuropathy is also a very frequent DM complication and its prevalence increases with DM duration [90]. The other important driver of DFUs is ischemia from peripheral arterial disease (PAD). Visual impairment, foot deformities and past history of DFU also increase the risk of DFUs [85, 86].

The underlying mechanisms of DFUs include diabetic neuropathy, PAD and

Diabetic neuropathy may affect the motor, sensory and autonomic nerves. Thickening of the basement membranes, endothelial hyperplasia in the vasa nervorum lead to thinning of the vascular lumen and secondary ischemia [90, 91]. On the other hand, metabolic disorders caused by chronic hyperglycemia, with the formation of AGEs, polyol pathways, increased oxidative stress levels and enzy-

Autonomic neuropathy causes arteriolo-venular shunts with secondary decreased blood flow in capillaries, but also anhidrosis, resulting in dry skin, thin, prone to cracking and ulceration. Sensory neuropathy leads to sensory (inability to feel warm/cold, pain, pressure), rendering the foot prone to undetected acute or chronic traumas [90, 91]. Motor neuropathy leads to imbalance between plantar flexors and extensors, with characteristic deformities, such as hammer toe, claw toe

etc, and leading to high planter pressures in some small foot areas [92–94].

PAD leads to lower-extremity ischemia. In diabetes, it is usually located in the infra-popliteal arteries, less so at the iliofemoral level [89, 95]. Ischemia portends

Pesently, micro and macrocirculatory disorders are considered not as separate entities, but more as a continuum in DM [97], neovascularization of vasa vasorum, with secondary hemorrhages and platelet aggregation facilitating the progression of

DFUs are frequently infected. The most common germs involved are staphylococci and streptococci, but deep infections are usually polymicrobial including gram positive, gram negative and even anaerobic germs [98, 99]. Chronic hypergly-

DFU represents any full-thickness ulcer below the ankle in DM. The initial signs and symptoms depend on the pathophysiological mechanism involved (neuropathy and/or PAD). Subjects with diabetic neuropathy are usually initially asymptomatic, but a minority of them may later develop neuropathic symptoms (numbness, paresthesia, lancinating or burning pain) with nocturnal exacerbation. In the event of PAD, intermittent claudication or even ischemic rest pain and gangrene may develop (**Figure 8**). Usually, DFUs develop in an area exposed to increased pressure, with a nonhealing tendency, often neglected in early stages due to diminished pain sensation. In the vent of infection, signs of local inflammation may be added (redness, swell-

Several staging systems were developed in order to characterize the pathogenic pathway and the severity and extension of ulcer. The International Working Group on the Diabetic Foot Risk Classification System (IWGDF) refers mainly at the severity of neuropathy and coexistence or not of the peripheral ischemia [100], while the Wagner classification describes the extension and depth [101] (**Tables 4** and **5**).

matic activation of PKC also have direct toxic effects on nerve fibers.

**264**

*Distal toe gangrene and extensive infection and inflammation at the level of the forefoot and mid foot (Dr. Dragos Serban's private collection).*


#### **Table 4.**

*IWGDF risk classification [96].*


#### **Table 5.**

*Wagner Classification of DFU [101].*

### **3.3 Diagnosis**

#### *3.3.1 Clinical examination*

Patient history is necessary to provide information on DM duration, glycemic control, associated risk factors and any prior lesions/amputations.

Clinical examination should look for skin disorders, foot deformities, nail lesions, blisters etc. also be documented. It must also include an evaluation of neuropathic deficits, PAD and infection. Signs of limb threatening infection include bullae, ecchymoses, soft tissue crepitus and rapid spread of infection [102, 103].

*Evaluation of sensory neuropathy* is very important to establish whether the patient has lost the protective sensation, making him prone to accidental trauma. Hot/cold discrimination, pain perception, light touch and vibration perception, as well as protective sensation must be tested [95–99]. The latter is best assessed by the 10 g Semmes Weinstein monofilament or the measurement of the vibration perception

threshold (VPT) with a neurothesiometer [93–95, 102, 103]. Tendon reflexes and muscular strength are also a part of the examination [95–99]. Finally, sudomotor dysfunction (reduced sweat production) is best examined by the Neuropad indicator test, which is based on a colour change from blue to pink [96, 97]. Indeed, this test has recently been identified as an independent risk factor of DFUs at 5 years [104].
